Approximately one in 2000 Caucasians have cystic fibrosis (CF), a genetic disorder caused by inactivating mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The CFTR protein, a member of the ABC transporter family, forms a chloride channel localized to the plasma membrane. The protein consists of five domains: two membrane-spanning domains that form the chloride ion channel, two nucleotide-binding domains that hydrolyze ATP, and a regulatory domain. Expression of the CFTR gene is highest in cells that line passageways of the lungs, pancreas, colon, ileum, and genitourinary tract.
In addition to CF, defects in the CFTR gene are associated with diseases including, for example, pancreatitis, chronic obstructive pulmonary disease (COPD), asthma, chronic sinusitis, primary sclerosing cholangitis, and congenital bilateral absence of the vas deferens (CBAVD).
The most common inactivating mutation of the CFTR gene, detected in about 70% of CF patients, is a deletion of the three base pairs encoding the phenylalanine at amino acid residue 508 (ΔF508). The F508 residue is located in a membrane spanning domain and its deletion causes incorrect folding of the newly synthesized protein. As a result, misfolded protein is degraded in the endoplasmic reticulum shortly after synthesis. Patients having a homozygous ΔF508 deletion tend to have the most severe symptoms of cystic fibrosis, resulting from a loss of chloride ion transport. The disturbance in the sodium and chloride ion balance in the cells lining the respiratory tract results in a thick, sticky mucus layer that is not easily removed by the cilia. The altered mucus also traps bacteria, resulting in chronic infections. Accordingly, most CF therapy is directed to controlling persistent and often fatal lung infections. There is a need for improved therapies that treat the underlying causes of CF and other CFTR-related diseases.